N-substituted azaheterocyclic carboxylic acids and esters thereof

ABSTRACT

The present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation.

This application is a divisional application of Ser. No. 08/367,648,filed Jan. 3, 1995, U.S. Pat. No. 5,595,989.

The present invention relates to novel N-substituted azaheterocycliccarboxylic acids and esters thereof in which a substituted alkyl chainforms part of the N-substituent or salts thereof, to methods for theirpreparation, to compositions containing them, and to their use for theclinical treatment of painful, hyperalgesic and/or inflammatoryconditions in which C-fibers play a pathophysiological role by elicitingneurogenic pain or inflammation.

BACKGROUND OF THE INVENTION

The nervous system exerts a profound effect on the inflammatoryresponse. Antidromic stimulation of sensory nerves results in localizedvasodilation and increased vascular permeability (Janecso et al. Br. J.Pharmacol. 1967, 31, 138-151) and a similar response is observedfollowing injection of peptides known to be present in sensory nerves.From this and other data it is postulated that peptides released fromsensory nerve endings mediate many inflammatory responses in tissueslike skin, joint, urinary tract, eye, meninges, gastro-intestinal andrespiratory tracts. Hence inhibition of sensory nerve peptide releaseand/or activity, may be useful in treatment of, for example arthritis,dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombophlelitis,glaucoma, gastro-intestinal diseases or migraine.

In U.S. Pat. No. 4,383,999 and No. 4,514,414 and in EP 236342 as well asin EP 231996 some derivatives ofN-(4,4-disubstituted-3-butenyl)-azaheterocyclic carboxylic acids areclaimed as inhibitors of GABA uptake. In EP 342635 and EP 374801,N-substituted azaheterocyclic carboxylic acids in which an oxime ethergroup and vinyl ether group forms part of the N-substituent respectivelyare claimed as inhibitors of GABA uptake. Further, in WO 9107389 and WO9220658, N-substituted azacyclic carboxylic acids are claimed as GABAuptake inhibitors. EP 221572 claims that1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.

In addition to the above cited references, U.S. Pat. No. 3,074,953discloses 1-(3-(10,11-dihydro-5H-dibenzoa,d!cyclohepten-5-ylidene)-1-propyl)-4-phenyl-4-piperidinecarboxylicacid ethyl ester as a psychotropic drug. Analogous 1-substituted4-phenyl-4-piperidinecarboxylic acid ester derivatives to the abovecited compound are described (J. Med. Chem. 1967, 10, 627-635 and J.Org. Chem. 1962, 27, 230-240) as analgesics, antispasmodics andpsychotropics. In JP 49032544, JP 48040357, FR 2121423, GB 1294550 andDE 2101066, 1-substituted 4-dialkylamino-4-piperidinecarboxamides aredisclosed as psychotropic agents, for the treatment of schizophrenia andas inhibitors of inflammation.

DESCRIPTION OF THE INVENTION

The present invention relates to novel N-substituted azaheterocycliccarboxylic acids and esters thereof of formula I ##STR1## wherein R¹ andR² independently are hydrogen, halogen, trifluoromethyl, C₁₋₆ -alkyl orC₁₋₆ -alkoxy; Y is >N-CH₂ --, >CH--CH₂ -- or >C═CH-- wherein only theunderscored atom participates in the ring system; X is --O--, --S--,--CR⁷ R⁸ --, --CH₂ CH₂ --, --CH═CH--CH₂ --, --CH₂ --CH═CH--, --CH₂ CH₂CH₂ --, --CH═CH--, --NR⁹ -- (C═O)--, --O--CH₂ --, --(C═O)-- or --(S═O)--wherein R⁷, R⁸ and R⁹ independently are hydrogen or C₁₋₆ -alkyl; r is 1,2, or 3; m is 1 or 2 and n is 1 when m is 1 and n is 0 when m is 2; R⁴and R⁵ each represents hydrogen or may--when m is 2--together representa bond; and R⁶ is OH or C₁₋₈ -alkoxy; or a pharmaceutically acceptablesalt thereof.

The compounds of formula I may exist as geometric and optical isomersand all isomers and mixtures thereof are included herein. Isomers may beseparated by means of standard methods such as chromatographictechniques or fractional crystallization of suitable salts.

Preferably, the compounds of formula I exist as the individual geometricor optical isomers.

The compounds according to the invention may optionally exist aspharmaceutically acceptable acid addition salts or--when the carboxylicacid group is not esterified--as pharmaceutically acceptable metal saltsor--optionally alkylated--ammonium salts.

Examples of such salts include inorganic and organic acid addition saltssuch as hydrochloride, hydrobromide, sulphate, phosphate, acetate,fumarate, maleate, citrate, lactate, tartrate, oxalate or similarpharmaceutically acceptable inorganic or organic acid addition salts,and include the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) which are hereby incorporated byreference.

As used herein, the term "patient" includes any mammal which couldbenefit from treatment of neurogenic inflammation. The term particularlyrefers to a human patient, but is not intended to be so limited.

It has been demonstrated that the novel compounds of formula I inhibitneurogenic inflammation which involves the release of neuropeptides fromperipheral and central endings of sensory C-fibres. Experimentally thiscan be demonstrated in animal models of formalin induced pain or pawoedema (Wheeler and Cowan, Agents Actions 1991, 34, 264-269) in whichthe novel compounds of formula I exhibit a potent inhibitory effect.Compounds of formula I may be used to treat all painful, hyperalgesicand/or inflammatory conditions in which C-fibers play apathophysiological role by eliciting neurogenic pain or inflammation,i.e.:

Acutely painful conditions exemplified by migraine, postoperative pain,burns, bruises, post-herpetic pain (Zoster) and pain as it is generallyassociated with acute inflammation; chronic, painful and/or inflammatoryconditions exemplified by various types of neuropathy (diabetic,post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis,gout, inflammatory bowel disease, prostatitis, cancer pain, chronicheadache, coughing, asthma, chronic pancreatitis, inflammatory skindisease including psoriasis and autoimmune dermatoses, osteoporoticpain.

The compounds of formula I may be prepared by the following method:##STR2##

A compound of formula II wherein R¹, R², X, Y, and r are as definedabove and W is a suitable leaving group such as halogen, p-toluenesulphonate or mesylate may be reacted with an azaheterocyclic compoundof formula III wherein R⁴, R⁵, R⁶, m and n are as defined above. Thisalkylation reaction may be carried out in a solvent such as acetone,dibutylether, 2-butanone, methyl ethyl ketone, ethyl acetate,tetrahydrofuran (THF) or toluene in the presence of a base e.g.potassium carbonate and a catalyst, e.g. an alkali metal iodide at atemperature up to reflux temperature for the solvent used for e.g. 1 to120 h. If esters have been prepared in which R⁶ is alkoxy, compounds offormula I wherein R⁶ is OH may be prepared by hydrolysis of the estergroup, preferably at room temperature in a mixture of an aqueous alkalimetal hydroxide solution and an alcohol such as methanol or ethanol, forexample, for about 0.5 to 6 h.

Compounds of formula II and III may readily be prepared by methodsfamiliar to those skilled in the art.

Under certain circumstances it may be necessary to protect theintermediates used in the above methods e.g. a compound of formula Illwith suitable protecting groups. The carboxylic acid group can, forexample, be esterified. Introduction and removal of such groups isdescribed in "Protective Groups in Organic Chemistry" J. F. W. McOrnieed. (New York, 1973).

Pharmacological Methods

Values for in vivo inhibition of formalin induced pain or oedema for thecompounds of the present invention were assessed in mice essentially bythe method of Wheeler-Aceto and Cowan (Agents Action 1991, 34, 265-269).

About 20 g NMRI female mice were injected 20 μl 1% formalin into theleft hind paw. The animals were then placed on a heated (31° C.) table,and the pain response was scored. After 1 h they were killed and bled.Left and right hind paws were removed and the weight difference betweenthe paws was used as indication of the oedema response of the formalininjected paw.

Values for inhibition of formalin induced pain response for somerepresentative compounds are recorded in table 1.

                  TABLE 1                                                         ______________________________________                                        Inhibition of formalin induced pain response at 0.1 mg/kg                     Example no.   % Pain inhibition                                               ______________________________________                                        4             50                                                              5             13                                                              7             35                                                              10            35                                                              11            29                                                              ______________________________________                                    

For the above indications the dosage will vary depending on the compoundof formula I employed, on the mode of administration and on the therapydesired. However, in general, satisfactory results are obtained with adosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mgto about 500 mg of compounds of formula I, conveniently given from 1 to5 times daily, optionally in sustained release form. Usually, dosageforms suitable for oral administration comprise from about 0.5 mg toabout 1000 mg, preferably from about 1 mg to about 500 mg of thecompounds of formula I admixed with a pharmaceutical carrier or diluent.

The compounds of formula I may be administered in a pharmaceuticallyacceptable acid addition salt form or where possible as a metal or alower alkylammonium salt. Such salt forms exhibit approximately the sameorder of activity as the free base forms.

This invention also relates to pharmaceutical compositions comprising acompound of formula I or a pharmaceutically acceptable salt thereof and,usually, such compositions also contain a pharmaceutical carrier ordiluent.

The compositions containing the compounds of this invention may beprepared by conventional techniques and appear in conventional forms,for example capsules, tablets, solutions or suspensions.

The pharmaceutical carrier employed may be a conventional solid orliquid carrier. Examples of solid carriers are lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate andstearic acid. Examples of liquid carriers are syrup, peanut oil, oliveoil and water.

Similarly, the carrier or diluent may include any time delay materialknown to the art, such as glyceryl monostearate or glyceryl distearate,alone or mixed with a wax.

If a solid carrier for oral administration is used, the preparation canbe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will usually be from about 25 mg to about 1g. If a liquid carrier is used, the preparation may be in the form of asyrup, emulsion, soft gelatin capsule or sterile injectable liquid suchas an aqueous or non-aqueous liquid suspension or solution.

Generally, the compounds of this invention are dispensed in unit dosageform comprising 50-200 mg of active ingredient in or together with apharmaceutically acceptable carrier per unit dosage.

The dosage of the compounds according to this invention is 1-500 mg/day,e.g. about 100 mg per dose, when administered to patients, e.g. humans,as a drug.

A typical tablet which may be prepared by conventional tablettingtechniques contains

    ______________________________________                                        Core:                                                                         Active compound (as free compound or salt thereof)                                                            100    mg                                     Colloidal silicon dioxide (Areosil ®)                                                                     1.5    mg                                     Cellulose, microcryst. (Avicel ®)                                                                         70     mg                                     Modified cellulose gum (Ac-Di-Sol ®)                                                                      7.5    mg                                     Magnesium stearate                                                            Coating:                                                                      HPMC                    approx. 9      mg                                     *Mywacett ® 9-40 T  approx. 0.9    mg                                     ______________________________________                                         *Acylated monoglyceride used as plasticizer for film coating.            

The route of administration may be any route which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral or parenteral e.g. rectal, transdermal,subcutaneous, intranasal, intramuscular, intravenous, intraurethral,ophthalmic solution or an ointment, the oral route being preferred.

EXAMPLES

The process for preparing compounds of formula I and preparationscontaining them is further illustrated in the following examples, which,however, are not to be construed as limiting.

Hereinafter, TLC is thin layer chromatography and THF istetrahydrofuran, CDCl₃ is deuterio chloroform and DMSO-d₆ ishexadeuterio dimethylsulfoxide. The structures of the compounds areconfirmed by either elemental analysis or NMR, where peaks assigned tocharacteristic protons in the title compounds are presented whereappropriate. ¹ H-NMR shifts (δ_(H)) are given in parts per million(ppm). M.p. is melting point and is given in °C. and is not corrected.Column chromatography was carried out using the technique described byW. C. Still et al, J. Org. Chem. (1978), 43, 2923-2925 on Merck silicagel 60 (Art. 9385). HPLC analysis was performed using a 5 μm C18 4×250mm column, eluting with a 20-80% gradient of 0.1% trifluoroaceticacid/acetonitrile and 0.1% trifluoroacetic acid/water over 30 minutes at35° C. Compounds used as starting materials are either known compoundsor compounds which can readily be prepared by methods known per se.

EXAMPLE 1a

(R)-1-(3-(10,11-Dihydro-5H-dibenzoa,d!cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acidhydrochloride

A solution of cyclopropylmagnesium bromide in dry THF (prepared fromcyclopropylbromide (12.1 g, 0.10 mol), magnesium turnings (2.45 g, 0.10mol) and dry THF (65 ml)) was placed under an atmosphere of nitrogen. Asolution of 10,11-dihydro-5H-dibenzo a,d!cyclohepten-5-one (10.4 g, 0.05mol) in dry THF (25 ml) was added dropwise and when addition wascomplete the mixture was heated at reflux for 30 minutes. The reactionmixture was cooled on an ice-bath and saturated ammonium chloride (50ml) was carefully added. The mixture was neutralized with 2Nhydrochloric acid and extracted with diethyl ether (2×200 ml). Thecombined organic extracts were dried (Na₂ SO₄) and the solvent wasevaporated in vacuo to give 13.1 g of crude5-cyclopropyl-10,11-dihydro-5H-dibenzo a,d!cyclohepten-5-ol.

The above crude alcohol (13.1 g) was dissolved in dichloromethane (150ml) and a solution of trimethylsilyl bromide (9.2 g, 0.06 mol) indichloromethane (50 ml) was added dropwise. When addition was completethe mixture was stirred at room temperature for 15 minutes and water (50ml) was added. The phases were separated and the organic phase waswashed with saturated sodium bicarbonate (2×50 ml). The organic phasewas dried (Na₂ SO₄) and the solvent was evaporated in vacuo to give 16.5g of crude 5-(3-bromo-1-propylidene)-10,11-dihydro-5H-dibenzoa,d!cycloheptene as a solid.

A mixture of the above crude bromide (6.3 g, 20 mmol), ethyl(R)-3-piperidinecarboxylate (4.7 g, 30 mmol), potassium carbonate (5.5g, 40 mmol) and acetone (50 ml) was stirred at room temperature for 124h. The mixture was filtered and the solvent was evaporated in vacuo. Theoily residue was purified on silica gel (200 g, ethylacetate/n-heptane=1/1) to give 4.4 g of(R)-1-(3-(10,11-dihydro-5H-dibenzoa,d!cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid ethylester as an oil. R_(f) =0.38 (SiO₂ ;-ethyl acetate/n-heptane=1:1).

The above ester (4.4 g, 11 mmol) was dissolved in ethanol (40 ml) and 4Nsodium hydroxide (8.3 ml) was added. The mixture was stirred vigorouslyat ambient temperature for 7 h. Dichloromethane (700 ml) was addedfollowed by 2.5N hydrochloric acid until pH 1. The phases wereseparated, the organic phase dried (MgSO₄) and the solvent wasevaporated in vacuo. The residue was re-evaporated twice with acetoneand then triturated with a mixture of acetone and diethyl ether. Thesolid was isolated by filtration and dried in air to give 2.2 g of thetitle compound as a solid.

M.p. 206°-208° C. Calculated for C₂₄ H₂₇ NO₂,HCl C, 72.4%; H, 7.1%; N,3.5%; Found: C, 72.1%; H, 7.3%; N, 3.3%.

By a similar procedure as described in Example 1a the followingcompounds have been prepared:

EXAMPLE 1b

(S)-1-(3-(10,11-Dihydro-5H-dibenzoa,d!cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic aciddihydrochloride

M.p. 216°-218° C. ¹ H-NMR (200 MHz, DMSO-d₆) δ_(H) 1.43 (bs, 1H), 1.78(bs, 2H), 1.96 (bs, 1H), 2.5 (bd, 1H, CH--COOH), 2.84 (bm, 2H), 3.16(bs, 2H), 3.26 (bs, 4H), 3.34 (s, 4H), 5.78 (t, 1H), 7.07 (dd, 1H,C═CH--CH₂), 7.12-7.29 (m, 7H).

EXAMPLE 1c

1-(3-(10,11-Dihydro-5H-dibenzoa,d!cyclohepten-5-ylidene)-1-propyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylicacid hydrochloride

M.p. 140°-145° C. Calculated for C₂₄ H₂₅ NO₂,HCl,C₃ H₆ O: C, 71.4%; H,7.1%; N, 3.1%; Found: C, 71.5%; H, 6.9%; N, 3.1%.

EXAMPLE 1d

(R)-1-(3-(Fluoren-9-ylidene)-1-propyl)-3-piperidinecarboxylic acidhydrochloride

M.p. 217°-219° C. Calculated for C₂₂ H₂₃ NO₂, HCl, 1/4H₂ O: C, 70.6%; H,6.5%; N, 3.7%; Cl, 9.5%; Found: C, 70.8%; H, 6.6%; N, 3.5%; Cl, 9.4%.

EXAMPLE 1e

(R)-1-(3-(3-Methyl-10,11-dihydro-5H-dibenzoa,d!cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acidhydrochloride

M.p. 218°-221° C. Calculated for C₂₄ H₂₉ NO₂, HCl: C, 72.87%; H, 7.35%;N, 3.40%; Found: C, 72.60%; H, 7.58%; N, 3.24%.

EXAMPLE 2

1-(3-(5H-Dibenzoa,d!cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid sodiumsalt

A solution of cyclopropylmagnesium bromide in dry THF (prepared fromcyclopropylbromide (8.0 g, 0.067 mol), magnesium turnings (1.3 g, 0.053mol) and dry THF (35 ml)) was placed under an atmosphere of nitrogen. Asolution of 5H-dibenzo a,d!cyclohepten-5-one (6.0 g, 0.028 mol) in dryTHF (15 ml) was added dropwise and when addition was complete themixture was heated at reflux for 30 minutes. The reaction mixture wascooled on an ice-bath and saturated ammonium chloride (35 ml) wascarefully added. The mixture was diluted with water (50 ml) andextracted with diethyl ether (2×50 ml). The combined organic extractswere washed with water, dried (Na₂ SO₄) and the solvent was evaporatedin vacuo to give 8.6 g of crude 5-cyclopropyl-5H-dibenzoa,d!cyclohepten-5-ol.

To the above crude alcohol (8.6 g) was added glacial acetic acid (60ml). The mixture was cooled on an ice-bath and a mixture of glacialacetic acid (30 ml) and 47% hydrobromic acid (15 ml) was added. Themixture was stirred for 30 minutes, poured into water (300 ml) andextracted with diethyl ether (2×100 ml). The combined organic phaseswere washed with water, dried (Na₂ SO₄) and the solvent was evaporatedin vacuo to give a residue which was recrystallized from diethyl ether.This afforded 6.8 g of 5-(3-bromo-1-propylidene)-5H-dibenzoa,d!cycloheptene as a solid. M.p. 88°-89° C.

A mixture of the above bromide (5.0 g, 16 mmol), ethyl3-piperidinecarboxylate (3.2 g, 20 mmol), potassium carbonate (7.3 g, 53mmol) and acetone (150 ml) was heated at reflux for 15 h. The mixturewas filtered and the solvent was evaporated in vacuo. The oily residuewas dissolved in ethyl acetate (60 ml) and washed with 2N hydrochloricacid (2×30 ml). The organic phase was dried and the solvent evaporatedin vacuo. The residue was dissolved in acetone (25 ml), treated withhydrogenchloride gas and the mixture was diluted with diethyl ether (120ml). The solvent was decanted and the oily residue was dried in vacuo togive 5.6 g of 1-(3-(5H-dibenzoa,d!cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid ethylester hydrochloride as an amorphous solid.

The above ester (4.5 g, 11 mmol) was dissolved in ethanol (80 ml), 32%sodium hydroxide (180 ml) was added and the mixture was heated at refluxfor 1 h. To the cooled reaction mixture a mixture of dichloromethane andethyl acetate was added. The phases were separated and the aqueous phasewas treated with activated charcoal and filtered through millipore (0.22μm). The solvent was evaporated from the filtrate in vacuo and theresidue was dissolved in a mixture of water and dichloromethane (1:3).The phases were separated, the organic phase dried (MgSO₄) and thesolvent evaporated in vacuo. The residue was dissolved in water andfreeze-dried to give 3.0 g of the title compound as an amorphous solid.

¹ H-NMR (DMSO-d₆) δ 5.47 (t, 1H); 6.94 (s, 2H).

EXAMPLE 3

1-(3-(Thioxanthen-9-ylidene)-1-propyl)-3-piperidinecarboxylic acidhydrochloride

A solution of cyclopropylmagnesium bromide in dry THF (prepared fromcyclopropylbromide (18.2 g, 0.15 mol), magnesium turnings (2.9 g, 0.12mol) and dry THF (80 ml)) was placed under an atmosphere of nitrogen. Asolution of thioxanthen-9-one (12.7 g, 0.06 mol) in dry THF (70 ml) wasadded dropwise and when addition was complete the mixture was heated atreflux for 20 minutes. The reaction mixture was cooled on an ice-bathand saturated ammonium chloride (70 ml) was carefully added. The mixturewas diluted with water (100 ml) and extracted with diethyl ether (2×100ml). The combined organic extracts were washed with water, dried (Na₂SO₄) and the solvent was evaporated in vacuo to give 25.2 g of crude9-cyclopropyl-9H-thioxanthen-9-ol.

To the above crude alcohol (25.2 g) was added glacial acetic acid (120ml). The mixture was cooled on an ice-bath and a mixture of glacialacetic acid (60 ml) and 47% hydrobromic acid (30 ml) was added. Themixture was stirred for 30 minutes, poured into water (600 ml) andextracted with diethyl ether (3×200 ml). The combined organic phaseswere washed with water, dried (Na₂ SO₄) and the solvent was evaporatedin vacuo to give 19.5 g of crude9-(3-bromo-1-propylidene)-9H-thioxanthene. R_(f) =0.35 (SiO₂ ;THF/heptane=1:9).

A mixture of the above crude bromide (2.0 g, 6.3 mmol), ethyl3-piperidinecarboxylate (1.2 g, 7.5 mmol), potassium carbonate (2.9 g,21 mmol) and acetone (60 ml) was stirred at ambient temperature for 3 hand then heated at reflux for 16 h. The mixture was filtered and thesolvent was evaporated in vacuo. The oily residue was purified on silicagel (dichloromethane/methanol=98:2) to give 1.3 g of1-(3-(thioxanthen-9-ylidene)-1-propyl)-3-piperidinecarboxylic acid ethylester as an oil. R_(f) =0.21 (SiO₂ ; dichloromethane/methanol=98:2).

The above ester (0.74 g, 1.8 mmol) was dissolved in ethanol (25 ml) and40% sodium hydroxide (6 ml) was added. The mixture was heated at refluxfor 1 h. 10% Hydrochloric acid (25 ml) was added followed bydichloromethane (150 ml). The phases were separated and the organicphase was washed with water, dried (NaSO₄) and the solvent wasevaporated in vacuo to give 0.6 g of the title compound as a solid. M.p.150°-160° C. A sample was dissolved in acetone and precipitated withdiethyl ether. The solid formed was isolated by filtration and dried invacuo.

Calculated for C₂₂ H₂₃ NO₂ S,HCl,1/2H₂ O: C, 64.3%; H, 6.1%; N, 3.4%;Found: C, 64.0%; H, 6.2%; N, 3.5%. ¹ H-NMR (CDCl₃) δ 5.74 (t, 1H).

EXAMPLE 4

(R)-1-(3-(10,11-Dihydro-5H-dibenzb,f!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid hydrochloride

To a solution of 10,11-dihydro-5H-dibenz b,f!azepine (8.1 g, 0.040 mol)in dry dibutyl ether (60 ml) kept under an atmosphere of nitrogen,sodium hydride (1.6 g, 0.040 mol, 60% oil dispersion) was carefullyadded. The reaction mixture was heated at reflux temperature for 4 h andthen allowed to cool to 80° C. 3-Bromo-1-propyl tetrahydro-2-pyranylether (10.7 g, 0.048 mol) was added and the mixture was heated at refluxtemperature for 16 h. To the cooled reaction mixture was added water (20ml) and the phases were separated. From the organic phase the solventwas evaporated and the residue was dissolved in a mixture of methanol(150 ml) and a 4N HCl solution (50 ml). The mixture was heated at refluxtemperature for 15 minutes and then stirred for 1 h at ambienttemperature. Water (250 ml) was added and the mixture was extracted withethyl acetate (2×200 ml). The combined organic extracts were dried (Na₂SO₄), filtered and the solvent evaporated in vacuo. This afforded aresidue which was purified further by chromatography on silica gel (200g) using a mixture of n-heptane and ethyl acetate (3:2) as eluent togive 5.5 g of 3-(10,11-dihydro-5H-dibenz b,f!azepin-5-yl)-1-propanol asan oil. R_(f) : 0.30 (SiO₂ ; n-heptane/ethyl acetate=1:1).

The above alcohol (3.0 g, 12 mmol) was dissolved in toluene (100 ml) andtriethylamine (4.0 ml) was added. Methanesulfonyl chloride (1.5 g, 19mmol) was added dropwise and when addition was complete the reactionmixture was stirred for 2 h. Water was added and the phases wereseparated. The organic phase was dried (MgSO₄) and the solvent wasevaporated in vacuo to give a residue which was dissolved in acetone (50ml). To this solution (R)-3-piperidinecarboxylic acid ethyl estertartrate (5.4 g, 18 mmol) and potassium carbonate (4.1 g, 30 mmol) wereadded and the mixture was heated at reflux for three days. The mixturewas allowed to cool, then filtered and the solvent evaporated in vacuoto give a residue which was dissolved in diethyl ether. The resultingmixture was extracted with a 5% tartaric acid solution (2×100 ml). Thecombined aqueous extracts were washed with diethyl ether and pH wasadjusted to 7-8 with potassium carbonate solution. The neutralisedaqueous mixture was extracted with ethyl acetate (2×200 ml). Thecombined ethyl acetate extracts were washed with water, brine and dried(MgSO₄). The solvent was evaporated in vacuo to give a residue which wasdissolved in diethyl ether (50 ml) and filtered through silica gel. Thisafforded 2.8 g of (R)-1-(3-(10,11-dihydro-5H-dibenzb,f!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester as anoil.

The above ester (2.8 g, 7.1 mmol) was dissolved in ethanol (10 ml) and4N sodium hydroxide (5.3 ml) was added. The mixture was stirred atambient temperature for 10 h and concentrated hydrochloric acid wasadded until acidic reaction (pH 1). The resulting mixture was extractedwith dichloromethane (300 ml) and the organic extract was dried (MgSO₄).The solvent was evaporated in vacuo to give a foamy residue which wasre-evaporated with acetone. This afforded 2.3 g of the title compound asan amorphous solid.

Calculated for C₂₃ H₂₈ N₂ O₂,HCl,H₂ O: C, 65.9%; H, 7.5%; N, 6.7%;Found: C, 66.1%; H, 7.6%; N, 6.2%.

EXAMPLE 5

(R)-1-(4-(10,11-Dihydro-5H-dibenzob,f!azepin-5-yl)-1-butyl)-3-piperidinecarboxylic acid hydrochloride

To a solution of 10,11-dihydro-5H-dibenzo b,f!azepine (16.2 g, 0.083mol) in dry dibutyl ether (120 ml) kept under an atmosphere of nitrogen,sodium hydride (3.2 g, 0.08 mol, 60% dispersion in oil) was carefullyadded. The reaction mixture was heated at reflux temperature for 4 h andthen allowed to cool to 80° C. 4-Chloro-1-butyl tetrahydro-2-pyranylether (18.5 g, 0.096 mol) was added and the mixture heated at refluxtemperature for 16 h. After cooling to room temperature, water (40 ml)was added, and the phases were separated. The organic phase wasevaporated until dryness. The residue was dissolved in a mixture ofmethanol (300 ml) and 4N HCl (100 ml). The mixture was heated at refluxtemperature for 15 minutes and then stirred for 1 h at room temperature.Water (500 ml) was added and the mixture was extracted with ethylacetate (6×200 ml). The combined organic extracts were dried (Na₂ SO₄),filtered and the solvent evaporated.

This afforded a residue which was purified by column chromatography onsilica gel (400 g) using a mixture of n-heptane and ethyl acetate (3:2)as eluent. 13.1 g (59%) of 4-(10,11-dihydro-5H-dibenzob,f!azepin-5-yl)-1-butanol was obtained as an oil, that solidified uponcooling in a refrigerator overnight. R_(f) : 0.34 (SiO₂ ;n-heptane/ethyl acetate=1:1).

The above alcohol (5.4 g, 0.02 mol) was dissolved in toluene (160 ml)and triethylamine (7 ml) was added. Methanesulfonyl chloride (2.5 ml,0.032 mol) was added dropwise and when addition was complete thereaction mixture was stirred for 2 h. Water was added and the phaseswere separated. The organic phase was dried (MgSO₄) and the solventevaporated in vacuo affording a residue which was dissolved in acetone(85 ml). To this solution (R)-3-piperidinecarboxylic acid ethyl estertartrate (9.0 g, 0.03 mol) and potassium carbonate (7.0 g, 0.051 mol)were added and the mixture was heated at reflux temperature for 16 h.After cooling to room temperature and filtration on filter aid (celite)the solvent was removed by evaporation. The residue was dissolved indiethyl ether (100 ml) and extracted with a 5% tartaric acid solution(3×125 ml). The combined aqueous extracts were washed with diethyl etherand pH was adjusted to 7-8 with a potassium carbonate solution. Theneutralised aqueous mixture was extracted with ethyl acetate (4×200 ml).The combined ethyl acetate extracts were washed with water, brine anddried (MgSO₄). The solvent was evaporated in vacuo affording 2.6 g (32%)of 1-(4-(10,11-dihydro-5H-dibenzob,f!azepin-5-yl)-1-butyl!-3-piperidinecarboxylic acid ethyl ester,obtained as an oil. The residue was purified further by columnchromatography on silica gel (65 g) using a mixture of dichloromethaneand methanol (99.2:0.8) as eluent. R_(f) : 0.20 (SiO₂ ; n-heptane/ethylacetate=1:1).

The above ester (1.5 g, 0.0037 mol) was dissolved in ethanol (10 ml) anda solution of NaOH (0.52 g) in water (2 ml) was added. The mixture wasstirred at room temperature for 2 h. Concentrated HCl was added untilpH<1 (2 ml). Dichloromethane (75 ml) was added, followed by water (50ml) and the phases were separated. The organic phase was dried (MgSO₄)and the solvent evaporated in vacuo. Acetone (15 ml) was added to theresidue which was re-evaporated. Acetone (30 ml) was added to the drywhite product, affording, after filtration and drying, 1.3 g (84%) ofthe title compound as a white solid.

M.p. 222°-224° C. Calculated for C₂₄ H₃₀ N₂ O₂, HCl: C, 69.47%; H,7.53%; N, 6.75%; Found: C, 69.26%; H, 7.88%; N, 6.50%.

EXAMPLE 6

(R)-1-(2-(10,11-Dihydro-5H-dibenzob,f!azepin-5-yl)ethyl)-3-piperidinecarboxylic acid hydrochloride

In a 500 ml roundbottom flask equipped with magnetical stirring,thermometer, addition funnel and scrubber 10,11-dihydro-5H-dibenzob,f!-azepine (19.5 g, 0.10 mol) was dissolved in dry toluene (100 ml).Chloroacetyl chloride (13.6 g, 0.12 mol) was slowly added. The reactionmixture was heated to 95° C. for 30 minutes and then allowed to cool toroom temperature. Under stirring, 0.2N NaOH (50 ml) was added. Moretoluene was added (100 ml) and the phases were separated. The organicphase was washed with 0.2N NaOH (3×50 ml) until pH>10, and then withwater (3×50 ml) and brine (50 ml). After drying (MgSO₄) the organicphase was evaporated in vacuo affording an oily residue thatcrystallised upon standing overnight. The product was obtained inquantitative yield and used for further reactions without purification.

The above crude amide (20.0 g, 0.074 mol) was dissolved in dry THF (150ml) under a nitrogen atmosphere and cooled to 5° C. Sodium borohydride(2.3 g, 0.06 mol) was added followed by slow dropwise addition of BF₃Et₂ O (9.4 ml, 0.076 mol). The reaction mixture was left stirringovernight. Further amounts of NaBH₄ (2.0 g. 0.053 mol) and BF₃ Et₂ O (6ml, 0.049 mol) were added, and stirring was continued overnight.Methanol (20 ml) was added dropwise and stirring was continued for 1 h.Water (80 ml) was added to dissolve precipitated salt, followed by ethylacetate (100 ml). The phases were separated, and the aquous phase wasextracted with ethyl acetate (2×100 ml). The combined organic extractswere washed with water (4×100 ml) and brine (100 ml). The solvent wasevaporated in vacuo and the residue was stripped twice with toluene. Thecrude product was purified by column chromatography on silica gel (400g) using dichloromethane as eluent. This afforded 15.0 g (79%) of5-(2-chloroethyl)-10,11-dihydro-5H-dibenzo b,f!azepine. R_(f) : 0.70(SiO₂ ; dichloromethane).

The above chloride (10.0 g, 0.039 mol) was dissolved in acetone (175 ml)and potassium iodide (3.3 g) was added. To this solution(R)-3-piperidinecarboxylic acid ethyl ester tartrate (18.0 g, 0.06 mol)and potassium carbonate (14.0 g, 0.12 mol) were added and the mixturewas heated at reflux temperature for 72 h. After cooling to roomtemperature and filtration on filter aid (celite) the solvent wasremoved by evaporation. The residue was purified by columnchromatography on silica gel (300 g) using a mixture of heptane andethyl acetate (1:1) as eluent. This afforded 1.6 g (11%) of(R)-1-(2-(10,11-dihydro-5H-dibenzo b,f!azepin-5-yl)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. R_(f) : 0.34 (SiO₂ ;n-heptane/ethyl acetate=1:1).

The above ester (1.28 g, 0.0034 mol) was dissolved in ethanol (10 ml)and a solution of NaOH (0.52 g) in water (2 ml) was added. The mixturewas stirred at room temperature for 2 h. Concentrated HCl was addeduntil pH<1 (2 ml). Dichloromethane (75 ml) was added, followed by water(50 ml) and the phases were separated. The organic phase was dried(MgSO₄) and the solvent evaporated in vacuo. Acetone (15 ml) was addedto the residue which was re-evaporated. Acetone (30 ml) was added to thedry white product, affording, after filtration and drying, 1.1 g (80%)of the title compound as a white solid.

M.p. 246°-248° C. Calculated for C₂₂ H₂₆ N₂ O₂, HCl, 1/4 H₂ O: C,67.44%; H, 7.02%; N, 7.15%; Found: C, 67.72%; H, 7.23%; N, 7.01%.

EXAMPLE 7

(R)-1-(3-(3-Chloro-10,11-dihydro-5H-dibenzob,f!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid hydrochloride

In a 100 ml roundbottom flask equipped with magnetical stirring,thermometer, nitrogen-inlet and addition funnel,3-chloro-10,11-dihydro-5H-dibenzo b,f!azepine (1.3 g, 0.0056 mol) wasdissolved in dry toluene (30 ml). Under nitrogen, ethyl malonyl chloride(1.01 g, 0.0067 mol) was slowly added. The reaction mixture was heatedat reflux temperature for 2 h and then allowed to cool to roomtemperature. Under stirring, 0.2N NaOH (2.5 ml) and water (30 ml) wasadded. More toluene was added (100 ml) and the phases were separated.The organic phase was washed with water (3×50 ml) and brine (50 ml).After drying (MgSO₄) the organic phase was evaporated in vacuo affordingan oily residue. The product was obtained in quantitative yield and usedfor further reactions without purification.

LiAlH₄ (920 mg, 0.024 mol) was placed in a dry 250 ml three-neckedroundbottom flask, equipped with thermometer, magnetical stirring andaddition funnel. Under nitrogen dry toluene (40 ml) was added followedby slow addition of THF (4 ml). A temperature at 15°-25° C. was assuredby the use of a water/ice-bath. The above amide (2.1 g, 0.0061 mol) wasdissolved in dry THF (12 ml) and slowly added to the LiAlH₄ -slurry. Thetemperature was kept at 20°-25° C. The reaction mixture was leftstirring overnight at room temperature. Water (1 ml) was added dropwise,followed by 4N NaOH (1 ml) and finally water (3 ml). The resultingprecipitate was filtered off on filter aid (celite) and the toluenesolution was dried (MgSO₄). The crude product was purified by columnchromatography on silica gel (75 g) using a mixture of heptane and ethylacetate (1:1) as eluent. This afforded 0.9 g (50%) of3-(3-chloro-10,11-dihydro-5H-dibenzo b,f!azepin-5-yl)-1-propanol as anoil. R_(f) : 0.36 (SiO₂ ; n-heptane/ethyl acetate=1:1).

The above alcohol (870 mg, 0.003 mol) was dissolved in toluene (25 ml)and triethylamine (1 ml) was added. Methanesulfonyl chloride (0.5 ml,0.006 mol) was added dropwise and the reaction mixture was stirred for 2h. Water (100 ml) was added, followed by further amounts of toluene (100ml) and the phases were separated. The organic phase was dried (MgSO₄)and the solvent evaporated in vacuo affording a residue which wasdissolved in methyl ethyl ketone (50 ml). To this solution(R)-3-piperidinecarboxylic acid ethyl ester tartrate (1.4 g, 0.0047 mol)and potassium carbonate (1.0 g, 0.0072 mol) were added and the mixturewas heated at reflux for 24 h, and left stirring at room temperature for24 h. After filtration on filter aid (celite) the solvent was removed byevaporation. The residue was purified by column chromatography on silicagel (100 g) using a mixture of heptane and ethyl acetate (1:1) aseluent. This afforded 1.0 g (79%) of(R)-1-(3-(3-chloro-10,11-dihydro-5H-dibenzob,f!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester as anoil. R_(f) : 0.34 (SiO₂ ; n-heptane/ethyl acetate=1:1).

The above ester (500 mg, 0.0012 mol) was dissolved in ethanol (4 ml) anda solution of NaOH (0.2 g) in water (1 ml) was added. The mixture wasstirred at room temperature for 2 h. Concentrated HCl was added untilpH<1 (0.75 ml). Dichloromethane (75 ml) was added followed by water (50ml) and the phases were separated. The organic phase was dried (MgSO₄)and the solvent evaporated in vacuo. The residue crystallized uponaddition of ethyl acetate, affording, after filtration and drying, 0.4 g(68%) of the title compound as a white solid.

M.p. 135°-138° C. Calculated for C₂₃ H₂₇ N₂ O₂, HCl, 3/4 H₂ O: C,61.48%; H, 6.57%; N, 6.23%; Found: C, 61.35%; H, 6.67%; N, 5.70%.

EXAMPLE 8a

(R)-1-(3-(10H-Phenothiazin-10-yl)-1-propyl)-3-piperidinecarboxylic acidhydrochloride

To a solution of phenothiazine (4.0 g, 0.02 mol) in drydimethylformamide (100 ml) kept under an atmosphere of nitrogen, sodiumhydride (1.0 g, 0.025 mol, 60% dispersion in oil) was carefully added.The reaction mixture was left stirring for 15 minutes.1-Bromo-3-chloropropane (8.0 g, 0.05 mol) was added and the mixture wasleft stirring overnight. Ammonium chloride (2.0 g, 0.04 mol) was added,and after continued stirring for 30 minutes the solution was poured ontowater (300 ml). The mixture was extracted with dichloromethane (2×200ml). The combined organic extracts were dried (MgSO₄), filtered and thesolvent evaporated. This afforded a residue which was purified by columnchromatography on silica gel (250 g) using a mixture of n-heptane andethyl acetate (9:1) as eluent. 4.4 g (80%) of10-(3-chloropropyl)-10H-phenothiazine was obtained as an oil. R_(f) :0.55 (SiO₂ ; n-heptane/ethyl acetate=1:1).

Potassium iodide (10.0 g, 0.06 mol) was dissolved in methyl ethyl ketone(100 ml) and heated at reflux temperature for 1 h. The above chloride(2.64 g, 0.09 mol) was dissolved in methyl ethyl ketone (10 ml) andadded. The mixture was heated at reflux temperature for 3 h. Aftercooling to about 60° C., (R)-3-piperidinecarboxylic acid ethyl estertartrate (2.64 g, 0.009 mol) and potassium carbonate (2.0 g, 0.014 mol)were added. The mixture was heated at reflux temperature for 24 h andleft stirring at room temperature for 24 h. After filtration on filteraid (celite) the solvent was removed by evaporation. The residue waspurified by column chromatography on silica gel (150 g) using a mixtureof heptane and ethyl acetate (6:4) as eluent. This afforded 2.5 g (87%)of (R)-1-(3-(10H-phenothiazin-10-yl)-1-propyl)-3-piperidinecarboxylicacid ethyl ester as an oil. R_(f) : 0.20 (SiO₂ ; n-heptane/ethylacetate=1:1).

The above ester (1.7 g, 0.0043 mol) was dissolved in ethanol (15 ml) anda solution of NaOH (0.63 g) in water (2.5 ml) was added. The mixture wasstirred at room temperature for 2 h. Concentrated HCl was added untilpH<1 (2.5 ml). Dichloromethane (100 ml) was added, followed by water (50ml) and the phases were separated. The organic phase was dried (MgSO₄)and the solvent evaporated in vacuo. The residue crystallized uponaddition of diethyl ether, followed by a small amount ofdichloromethane. This afforded, after filtration and drying, 0.3 g (18%)of the title compound as a white solid. Subsequent re-evaporation of thefiltrate afforded 1.08 g (62%) of the product.

M.p. 123°-128° C. Calculated for C₂₁ H₂₅ N₂ O₂ S, HCl, 5/4 H₂ O: C,58.95%; H, 6.43%; N, 6.55%; Found: C, 59.19%; H, 6.52%; N, 6.17%.

By a similar procedure as described in Example 8a the followingcompounds have been prepared:

EXAMPLE 8b

(R)-1-(3-(2-Trifluoromethyl-10H-phenothiazin-10-yl)-1-propyl)-3-piperidinecarboxylicacid hydrochloride

M.p. 198°-200° C. ¹ H-NMR (200 MHz, DMSO-d₆) δ_(H) 1.45 (bs, 1H),1.79-2.13 (bm, 4H), 2.76-3.44 (bm, 8H), 4.06 (t, 2H), 7.02 (t, 1H),7.12-7.42 (m, 6H).

EXAMPLE 8c

(R)-1-(3-(5-Oxo-10H-phenothiazin-10-yl)-1-propyl)-3-piperidinecarboxylicacid hydrochloride

10-(3-Chloropropyl)-10H-phenothiazine (2 g, 0.007 mol) was dissolved inglacial acetic acid (40 ml), 30% aqueous hydrogen peroxide (2.25 ml,0.022 mol) was added and the mixture stirred for 48 h under anatmosphere of nitrogen. The reaction mixture was left overnight.Precipitated crystals were filtered off and washed with water (2×20 ml),diethyl ether (2×50 ml) and dried in vacuo. Yield 1.38 g (64%) of10-(3-chloropropyl)-10H-phenothiazine 5-oxide as light brown crystals.M.p. 171°-173° C.

¹ H-NMR (200 MHz, CDCl₃) δ_(H) 2.35 (m, 2H), 3.63 (t, 2H), 4.43 (t, 2H),7.25 (t, 2H), 7.40 (d, 2H), 7.61 (dt, 2H), 8.09 (dd, 2H).

The title compound was prepared using10-(3-chloropropyl)-10H-phenothiazine 5-oxide instead of10-(3-chloropropyl)-10H-phenothiazine by a method similar to thatdescribed in Example 8a.

M.p.>280° C. ¹ H-NMR (400 MHz, DMSO-d₆) δ_(H) 1.46 (bd, 1H), 1.84 (bs,2H), 2.01 (bd, 1H), 2.28 (bs, 2H), 2.89 (bd, 2H), 3.39 (bm, 2H), 3.54(bd, 1H), 4.39 (t, 2H, N--CH₂ --CH₂ --), 7.41 (m, 2H), 7.79 (d, 4H),8.03 (d, 2H), 10.95 (bs, 1H), 12.85 (bs, 1H).

EXAMPLE 9

(R)-1-(3-(10H-Phenoxazin-10-yl)-1-propyl)-3-piperidinecarboxylic acidhydrochloride

To a solution of phenoxazine (3.7 g, 0.02 mol) in dry dimethylformamide(100 ml) kept under an atmosphere of nitrogen, sodium hydride (1.2 g,0.03 mol, 60% dispersion in oil) was carefully added. The reactionmixture was left stirring for 15 minutes. 1-Bromo-3-chloro-propane (8.0g, 0.05 mol) was added and the mixture was left stirring overnight.Ammonium chloride (2.0 g, 0.04 mol) was added, and after continuedstirring for 30 minutes, the solution was poured onto water (300 ml).The mixture was extracted with dichloromethane (2×200 ml). The combinedorganic extracts were dried (MgSO₄), filtered and the solvent evaporatedin vacuo. 10-(3-Chloropropyl)-10H-phenoxazine was obtained inquantitative yield as an oil and used without further purification.R_(f) : 0.68 (SiO₂ ; n-heptane/ethyl acetate=1:1).

Potassium iodide (10.0 g, 0.06 mol) was dissolved in methyl ethyl ketone(100 ml) and heated at reflux temperature for 1 h. The above chloride(5.2 g, 0.02 mol) was dissolved in methyl ethyl ketone (10 ml) andadded. The mixture was heated at reflux temperature for 3 h. Aftercooling to about 60° C., (R)-3-piperidinecarboxylic acid ethyl estertartrate (5.3 g, 0.0018 mol) and potassium carbonate (4.0 g, 0.028 mol)were added. The mixture was heated at reflux temperature for 24 h, andleft stirring at room temperature for 24 h. After filtration on filteraid (celite) the solvent was removed by evaporation in vacuo. Theresidue was purified by column chromatography on silica gel (250 g)using a mixture of heptane and ethyl acetate (1:1) as eluent. Thisafforded 5.2 g (67%) of(R)-1-(3-(10H-phenoxazin-10-yl)-1-propyl)-3-piperidinecarboxylic acidethyl ester as an oil. R_(f) : 0.25 (SiO₂ ; n-heptane/ethylacetate=1:1).

The above ester (2.34 g, 0.006 mol) was dissolved in ethanol (25 ml) andand a solution of NaOH (0.9 g) in water (3.5 ml) was added. The mixturewas stirred at room temperature for 2 h. Concentrated HCl was addeduntil pH<1 (3.5 ml). Dichloromethane (150 ml) was added, followed bywater (70 ml) and the phases were separated. The organic phase was dried(MgSO₄) and the solvent evaporated in vacuo, affording 1.8 g (77%) ofproduct. To further purify the product, it was washed with diethylether, ethyl acetate and subsequently acetone, affording 1.2 g (50%) ofthe title compound.

M.p. 217°-220° C. Calculated for C₂₁ H₂₄ N₂ O₃, HCl: C, 64.86%; H,6.48%:, N, 7.20%; Found: C, 64.56%; H, 6.70%; N, 6.89%.

EXAMPLE 10

(S)-1-(3-(10,11-Dihydro-5H-dibenzob,f!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid hydrochloride

To a solution of 10,11-dihydro-5H-dibenzo b,f!azepine (8.1 g, 0.040 mol)in dry dibutyl ether (60 ml) kept under an atmosphere of nitrogen,sodium hydride (1.6 g, 0.04 mol, 60% dispersion in oil) was carefullyadded. The reaction mixture was heated at reflux temperature for 4 h andthen allowed to cool to 80° C. 3-Bromo-1-propyl tetrahydro-2-pyranylether (10.7 g, 0.048 mol) was added and the mixture was heated at refluxtemperature for 16 h. After cooling to room temperature, water (20 ml)was added, and the phases were separated. The organic phase wasevaporated until dryness. The residue was dissolved in a mixture ofmethanol (150 ml) and 4N HCl (50 ml). The mixture was heated at refluxtemperature for 15 minutes and then stirred for 1 h at room temperature.Water (250 ml) was added and the mixture was extracted with ethylacetate (2×200 ml). The combined organic extracts were dried (Na₂ SO₄),filtered and the solvent evaporated in vacuo. This afforded a residuewhich was purified by column chromatography on silica gel (200 g) usinga mixture of n-heptane and ethyl acetate (3:2) as eluent. This afforded5.5 g (54%) of 3-(10,11-dihydro-5H-dibenzo b,f!azepin-5-yl)-1-propanolas an oil, that solidified upon cooling in a refrigerator overnight.R_(f) : 0.30 (SiO₂ ; n-heptane/ethyl acetate=1:1).

The above alcohol (2.5 g, 0.0099 mol) was dissolved in dry THF (20 ml)and triethylamine (2.0 ml) was added under a nitrogen atmosphere.Methanesulfonyl chloride (0.77 ml, 0.0099 mol) was added dropwise andwhen addition was complete the reaction mixture was stirred for 45minutes and then filtered. Triethylamine (3.4 ml) was added to thefiltrate, followed by (S)-3-piperidinecarboxylic acid ethyl estertartrate (4.55 g, 0.015 mol). The mixture was heated at refluxtemperature for 48 h, and left at room temperature for 7 days. Afterfiltration on filter aid (celite) the solvent was removed by evaporationin vacuo. The residue was purified further by column chromatography onsilica gel (200 g) using a mixture of dichloromethane and methanol (9:1)as eluent, affording 0.4 g (9%) of (S)-1-(3-(10,11-dihydro-5H-dibenzob,f!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester as anoil. R_(f) : 0.30 (SiO₂ ; dichloromethane/methanol=9:1).

The above ester (0.35 g, 0.89 mmol) was dissolved in ethanol (3 ml) and12N NaOH (0.26 ml) was added. The mixture was stirred at roomtemperature for 1.5 h and 4N HCl was added until pH<1 (1 ml).Dichloromethane (50 ml) was added and the phases were separated. Theorganic phase was dried (MgSO₄) and the solvent evaporated in vacuo. Theresidue was re-evaporated twice with acetone, affording after drying 0.2g (62%) of the title compound as a white amorphous product.

HPLC retention time=21.36 minutes. Calculated for C₂₃ H₂₈ N₂ O₂, HCl,3/4 H₂ O: C, 66.65%; H, 7.42%; N, 6.76%; Found: C, 66.99%; H, 7.48%; N,6.36%.

EXAMPLE 11

1-(3-(10,11-Dihydro-5H-dibenzob,f!azepin-5-yl)-1-propyl)-3-pyrrolidinacetic acid hydrochloride

3-(10,11-Dihydro-5H-dibenzo b,f!azepin-5-yl)-1-propanol (2.0 g, 0.0079mol, prepared as described in example 10) was dissolved in dry THF (25ml) under an atmosphere of nitrogen, and triethylamine (2.75 ml) wasadded. Methanesulfonyl chloride (0.61 ml, 0.0079 mol) was added dropwiseand when addition was complete the reaction mixture was stirred for 45minutes. The mixture was filtered and 3-pyrrolidinacetic acid methylester (2.4 g, 0.012 mol) was added to the filtrate. The mixture washeated at reflux temperature for 4 h and then stirred at roomtemperature for 48 h. Triethylamine (2.2 ml) was added and the mixturewas heated at reflux temperature for 24 h. After cooling to roomtemperature the solvent was removed by evaporation in vacuo. The residuewas purified by column chromatography on silica gel (125 g) using amixture of dichloromethane and methanol (9:1) as eluent, affording 0.9 g(27%) of 1-(3-(10,11-dihydro-5H-dibenzob,f!azepin-5-yl)-1-propyl)-3-pyrrolidinacetic acid methyl ester as anoil. R_(f) : 0.15 (SiO₂ ; dichloromethane/methanol/acetic acid=20:2:1).

The above ester (0.85 g, 0.0022 mol) was dissolved in ethanol (6 ml) and0.5N NaOH was added. By continued addition of 0.25N NaOH pH was kept atapproximately 12 for 3 days. Dilute HCl (approx. 1N) was added untilpH=7, and the solvent was evaporated in vacuo. The residue was purifiedby column chromatography on silica gel (50 g) using a mixture ofdichloromethane, methanol and acetic acid (20:2:1) as eluent. Theproduct fractions were stripped with dichloromethane, affording 0.04 g(3.8%) of 1-(3-(10,11-dihydro-5H-dibenzob,f!azepin-5-yl)-1-propyl)-3-pyrrolidinacetic acid as an amorphousproduct.

HPLC retention time=21.66 minutes. ¹ H-NMR (400 MHz, CDCl₃) δ_(H) 168(1H, m), 2.01 (2H, m), 2.15 (2H, m), 2.38 (2H, m), 2.63 (1H, m), 2.81(1H, m), 2.95 (2H, m), 3.13 (6H, m), 3.80 (2H, t), 6.92 (2H, t), 7.01(2H, m), 7.06-7.18 (4H, m).

EXAMPLE 12

(R)-1-(3-(11H-10-Oxa-5-aza-5H-dibenzoa,d!cyclohepten-5-yl)-1-propyl)-3-piperidinecarboxylic acidhydrochloride

In a 500 ml roundbottom flask equipped with magnetical stirring,thermometer and addition funnel 5,11-dihydro-10-oxa-5-azadibenzoa,d!cycloheptene (4.0 g, 0.02 mol, prepared in a similar way asdescribed in J.Med. Chem., 7, (1964), 609) was dissolved in dry toluene(50 ml) and 3-bromopropionyl chloride (4.2 g, 0.024 mol) was slowlyadded. The reaction mixture was heated to 95° C. for 30 minutes and thenallowed to cool to room temperature. Under stirring 0.2N NaOH (10 ml)was added. More toluene was added (50 ml) and the phases were separated.The organic phase was washed with 0.2N NaOH (3×20 ml) until pH>10, andthen with water (3×20 ml) and brine (20 ml). After drying (MgSO₄), theorganic phase was evaporated in vacuo affording an oil. The product wasobtained in quantitative yield and used for further reactions withoutpurification.

The above amide (3.5 g, 0.01 mol) was dissolved in dry THF (20 ml) undera nitrogen atmosphere and cooled to 5° C. Sodium borohydride (0.31 g,0.008 mol) was added followed by slow dropwise addition of borontrifluoride etherate (2.0 ml, 0.016 mol). The reaction mixture was leftstirring overnight. Further amounts of sodium borohydride (1.2 g. 0.032mol) and boron trifluoride etherate (5 ml, 0.040 mol) were supplied, andstirring was continued overnight. Water was added to dissolveprecipitated salt, followed by ethyl acetate (100 ml). The phases wereseparated, and the aqueous phase was extracted with ethyl acetate (2×100ml). The combined organic extracts were washed with water (4×100 ml) andbrine (100 ml). After drying (MgSO₄) the solvent was removed byevaporation in vacuo and the crude product was purified by columnchromatography on silica gel (200 g) with dichloromethane as eluent.This afforded 0.8 g (13%) of the product,3-bromo-1-(11H-10-oxa-5-aza-5H-dibenzo a,d!cyclohepten-5-yl)propane.R_(f) : 0.62 (SiO₂ ; dichloromethane).

Potassium iodide (3.0 g, 0.018 mol) was dissolved in methyl ethyl ketone(50 ml) and heated at reflux temperature for 30 minutes. The abovebromide (0.8 g, 0.0025 mol) was dissolved in methyl ethyl ketone (20ml), and added. The mixture was heated at reflux temperature for 90minutes. After cooling to about 60° C., (R)-3-piperidinecarboxylic acidethyl ester tartrate (0.8 g, 0.0027 mol) and potassium carbonate (0.62g, 0.0053 mol) were added. The mixture was heated at reflux temperaturefor 24 h, and left stirring at room temperature for 48 h. Afterfiltration on filter aid (celite) the solvent was removed by evaporationin vacuo. The residue was purified by column chromatography on silicagel (100 g) using a mixture of heptane and ethyl acetate (1:1) aseluent. This afforded 0.4 g (37%) of(R)-1-(3-(11H-10-oxa-5-aza-5H-dibenzoa,d!cyclohepten-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl esteras an oil. R_(f) : 0.17 (SiO₂ ; n-heptane/ethyl acetate=1:1).

The above ester (0.37 g, 0.00094 mol) was dissolved in ethanol (5 ml)and a solution of NaOH (0.13 g) in water (0.5 ml) was added. The mixturewas stirred at room temperature for 2 h. Concentrated HCl was addeduntil pH<1 (0.5 ml). Dichloromethane (50 ml) was added, followed bywater (10 ml) and the phases were separated. The organic phase was dried(MgSO₄) and the solvent evaporated in vacuo. The residue wasre-evaporated twice with acetone and once with ethyl acetate, affording,after drying, 0.3 g (77%) of the title compound as an amorphouscompound.

HPLC retention time=22.57 minutes Calculated for C₂₂ H₂₆ N₂ O₃, HCl, 1/2C₄ H₈ O₂ : C, 64.49%; H, 6.99%; N, 6.27%; Found: C, 64:32%; H, 7.05%; N,5.99%.

EXAMPLE 13

1-(3-(10,11-Dihydro-5H-dibenzob,f!azepin-5-yl)-1-propyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acidhydrochloride

3-(10,11-Dihydro-5H-dibenzo b,f!azepin-5-yl)-1-propanol (1.75 g, 0.0069mol, prepared as described in Example 4) was dissolved in THF (20 ml)and kept under an atmosphere of nitrogen. Triethylamine (1.44 ml) wasadded, followed by dropwise addition of methanesulfonyl chloride (0.54ml, 0.0069 mol). When addition was complete the reaction mixture wasstirred for 45 minutes. The reaction mixture was filtered and1,2,5,6-tetrahydro-3-pyridinecarboxylic acid ethyl ester hydrochloride(1.99 g, 0.01 mol) and triethylamine (2.4 ml) were added. The mixturewas stirred at room temperature for 9 days. More THF was added, thereaction mixture was filtered and the solvent was removed by evaporationin vacuo. The residue was purified by column chromatography on silicagel (100 g) using a mixture of heptane and ethyl acetate (1:1) aseluent. This afforded 2.1 g (78%) of 1-(3-(10,11-dihydro-5H-dibenzob,f!azepin-5-yl)-1-propyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acidethyl ester as an oil. R_(f) : 0.25 (SiO₂ ; n-heptane/ethylacetate=1:1).

The above ester (1.7 g, 0.0044 mol) was dissolved in ethanol (10 ml) and4N NaOH (2.7 ml) was added. The mixture was stirred at room temperaturefor 3 h. 4N HCl (3.8 ml) was added followed by dichloromethane (100 ml)and the phases were separated. The organic phase was dried (MgSO₄) andthe solvent evaporated in vacuo, affording 1.3 g (76%) of the titlecompound as a white amorphous product.

HPLC retention time=21.16 minutes Calculated for C₂₃ H₂₆ N₂ O₂, HCl, H₂O: C, 66.26%; H, 7.01%; N, 6.72%; Found: C, 66.57%; H. 7.21%; N, 6.33%.

EXAMPLE 14

(R)-1-(3-(6,7-Dihydro-5H-dibenzob,g!azocin-12-yl)-1-propyl)-3-piperidinecarboxylic acid hydrochloride

In a 100 ml roundbottom flask equipped with magnetical stirring,thermometer and addition funnel, 5,6,7,12-tetrahydrodibenzo b,g!azocine(2.1 g, 0.01 mol, prepared in a similar way as described in Chem. Pharm.Bull., 26, (1978), 942) was dissolved in dry toluene (60 ml) and ethylmalonyl chloride (2.0 g, 0.013 mol) was slowly added. The reactionmixture was heated at reflux temperature for 2 h and then allowed tocool to room temperature. Under stirring, 0.2N NaOH (5 ml) and water (60ml) were added. More toluene was added (100 ml) and the phases wereseparated. The organic phase was washed with water (3×75 ml) and brine(75 ml). After drying (MgSO₄), the organic phase was evaporated in vacuoaffording 3.1 g (95%) of 3-(6,7-dihydro-5H-dibenzob,g!azocin-12-yl)-3-oxopropionic acid ethyl ester as an oil.

LiAlH₄ (1.4 g, 0.037 mol) was placed in a dry, 250 ml, three-necked,roundbottom flask, equipped with thermometer, magnetical stirring andaddition funnel. Under nitrogen, dry toluene (60 ml) was added followedby slow addition of THF (6 ml). A temperature at 15°-25° C. was assuredby the use of a water/ice-bath. After stirring for 30 minutes, the aboveamide (3.0 g, 0.0093 mol) was dissolved in dry toluene (18 ml) andslowly added to the LiAlH₄ -slurry at 20°-25° C. The reaction mixturewas left stirring overnight at room temperature. Water (1.5 ml) wasslowly added dropwise, followed by 4N NaOH (1.5 ml) and finally water(4.5 ml). The resulting precipitate was filtered off on filter aid(celite). The toluene solution was dried (MgSO₄) and evaporated invacuo. The crude residue was purified by column chromatography on silicagel (75 g), using a mixture of heptane and ethyl acetate (1:1) aseluent. This afforded 0.4 g (48%) of 3-(6,7-dihydro-5H-dibenzob,g!azocin-12-yl)-1-propanol, as an oil. R_(f) : 0.37 (SiO₂ ;n-heptane/ethyl acetate=1:1)

The above alcohol (1.2 g, 0.0045 mol) was dissolved in toluene (25 ml)and triethylamine (1.5 ml) was added. Methanesulfonyl chloride (0.75 ml,0.009 mol) was added dropwise and the reaction mixture was stirred for 2h. Water (100 ml) was added, followed by further amounts of toluene (100ml) and the phases were separated. The organic phase was dried (MgSO₄)and the solvent evaporated in vacuo affording a residue which wasdissolved in methyl ethyl ketone (75 ml). To this solution,(R)-3-piperidinecarboxylic acid ethyl ester tartrate (2.1 g, 0.007 mol)and potassium carbonate (1.5 g, 0.011 mol) were added and the mixturewas heated at reflux temperature for 24 h, and left stirring at roomtemperature for 8 days. After filtration on filter aid (celite) thesolvent was removed by evaporation in vacuo. The residue was purified bycolumn chromatography on silica gel (75 g) using a mixture of heptaneand ethyl acetate (1:1) as eluent. This afforded 1.1 g (61%) of(R)-1-(3-(6,7-dihydro-5H-dibenzob,g!azocin-12-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester asan oil. R_(f) : 0.29 (SiO₂ ; n-heptane/ethyl acetate=1:1).

The above ester (500 mg, 0.0012 mol) was dissolved in ethanol (7 ml) anda solution of NaOH (0.2 g) in water (1.5 ml) was added. The mixture wasstirred at room temperature for 2 h, and concentrated HCl was addeduntil pH<1 (0.75 ml). Dichloromethane (100 ml) was added, followed bywater (50 ml) and the phases were separated. The organic phase was dried(MgSO₄) and the solvent evaporated in vacuo. The residue wasre-evaporated with acetone, ethyl acetate was added and the product wasfiltered and washed with diethyl ether. This afforded, after drying, 0.4g (71%) of the title compound as an amorphous compound.

HPLC retention time=22.70 minutes. Calculated for C₂₄ H₃₀ N₂ O₂, HCl,1/4 C₄ H₈ O2: C, 68.72%; H, 7.56%; N, 6.41%; Found: C, 69.12%; H, 7.94%;N, 6.12%.

EXAMPLE 15

(R)-1-(3-(10,11-Dihydro-5H-dibenzoa,d!cyclohepten-5-yl)-1-propyl)-3-piperidinecarboxylic acidhydrochloride

In a 50 ml roundbottom flask equipped with magnetical stirring,thermometer and addition funnel, sodium hydride (0.8 g, 0.02 mol, 60%dispersion in oil) was suspended in dry toluene under an atmosphere ofnitrogen. A solution of 10,11-dihydro-5H-dibenzoa,d!cycloheptene-5-carbonitrile (3.0 g, 0.014 mol, prepared in a similarway as described in J. Med. Chem., 6, (1963), 251) in dry toluene (15ml) was added. The reaction mixture was heated to reflux temperature in30 minutes and then heated at reflux temperature for 150 minutes. Aftercooling to about 50° C., a solution of 3-bromopropyl tetrahydropyranylether (4.5 g, 0.02 mol) in dry toluene (6 ml) was added dropwise. Thereaction mixture was heated at reflux temperature for 5 h and then leftstirring at room temperature overnight. After filtration of precipitatedsalts, the solution was washed with 1N HCl (100 ml), diluted with moretoluene (100 ml) and finally washed with water. After drying (MgSO₄),the organic phase was evaporated in vacuo affording 7.2 g (99%) of5-(3-(tetrahydropyran-2-yloxy) -1-propyl)-10,11-dihydro-5H-dibenzoa,d!cycloheptene-5-carbonitrile.

Under nitrogen, sodium amide (3.5 g, 0.045 mol, 50% suspension intoluene) was added to a 100 ml three-necked roundbottom flask. The abovenitrile (4.0 g, 0.011 mol) was dissolved in dry toluene (50 ml) andadded. The reaction mixture was heated at reflux temperature for 16 h.After cooling to room temperature, water was added with caution (100ml). More toluene was added and the organic phase was washed with diluteHCl. After drying (MgSO₄), the organic phase was evaporated in vacuoaffording 3.0 g (81%) of crude 2-(3-(10,11-dihydro-5H-dibenzoa,d!cyclohepten-5-yl)-1-propyloxy)tetrahydropyran as an oil.

The above tetrahydropyran (3.0 g, 0.009 mol) was dissolved in methanol(30 ml) and 4N HCl (10 ml) was added. The reaction mixture was heated atreflux temperature for 15 minutes and left stirring at room temperaturefor 1 h. Water (50 ml) was added and the aqueous phase was extractedwith ethyl acetate (3×75 ml). The combined organic extracts were dried(MgSO₄), filtered and the solvent evaporated in vacuo. This afforded aresidue which was purified by column chromatography on silica gel (100g) using a mixture of n-heptane and ethyl acetate (2:1) as eluent. Thisafforded 0.6 g (24%) of 3-(10,11-dihydro-5H-dibenzoa,d!cyclohepten-5-yl)-1-propanol as an oil. R_(f) : 0.37 (SiO₂ ;n-heptane/ethyl acetate=1:1).

The above alcohol (0.55 g, 0.002 mol) was dissolved in toluene (25 ml)and triethylamine (1 ml) was added. Methanesulfonyl chloride (0.5 ml,0.006 mol) was added dropwise and the reaction mixture was stirred for 2h. Water (75 ml) was added, followed by a further amount of toluene (100ml) and the phases were separated. The organic phase was dried (MgSO₄)and the solvent evaporated in vacuo affording a residue which wasdissolved in methyl ethyl ketone (50 ml). To this solution,(R)-3-piperidinecarboxylic acid ethyl ester tartrate (1.0 g, 0.0033 mol)and potassium carbonate (0.75 g, 0.0055 mol) were added and the mixturewas heated at reflux for 24 h, and then left stirring at roomtemperature for 72 h. After filtration on filter aid (hyflo) the solventwas removed by evaporation in vacuo. The residue was purified by columnchromatography on silica gel (50 g) using a mixture of heptane and ethylacetate (1:1) as eluent. This afforded 0.25 g (29%) of(R)-1-(3-(10,11-dihydro-5H-dibenzoa,d!cyclohepten-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl esteras an oil. R_(f) : 0.21 (SiO₂ ; n-heptane/ethyl acetate=1:1)

The above ester (240 mg, 0.00061 mol) was dissolved in ethanol (4 ml)and a solution of NaOH (0.1 g) in water (1 ml) was added. The mixturewas stirred at room temperature for 2 h and concentrated HCl was addeduntil pH<1 (0.4 ml). Dichloromethane (100 ml) was added, followed bywater (50 ml) and the phases were separated. The organic phase was dried(MgSO₄) and the solvent evaporated in vacuo. The residue wasre-evaporated with acetone, ethyl acetate was added and the product wasfiltered and washed with diethyl ether. This afforded, after drying, 0.2g (73%) of the title compound as an amorphous product.

MS(El) 363.2 (M⁺ - HCl, 15%). Calculated for C₂₄ H₂₉ NO₂, HCl, 3/2 H₂ O:C, 67.52%; H, 7.74%; N, 3.28%; Found: C, 67.70%; H, 7.77%; N, 3.44%.

EXAMPLE 16

(R)-1-(3(3-Methoxy-10,11-dihydro-5H-dibenzob,f!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid hydrochloride

In a 100 ml roundbottom flask equipped with magnetical stirring,thermometer, N₂ -inlet and addition funnel,3-methoxy-10,11-dihydro-5H-dibenzo b,f!azepine (1.2 g, 0.0053 mol) wasdissolved in dry toluene (30 ml). Under nitrogen, ethyl malonyl chloride(1.01 g, 0.0067 mol) was slowly added. The reaction mixture was heatedat reflux temperature for 2 h and then allowed to cool to roomtemperature. Under stirring a solution of 0.2N NaOH (2.5 ml) in water(30 ml) was added. More toluene was added (100 ml) and the phases wereseparated. The organic phase was washed with water (3×50 ml), and brine(50 ml). After drying (MgSO₄), the organic phase was evaporated in vacuoaffording an oily residue. The product was obtained in quantitativeyield and used for further reactions without purification.

LiAlH₄ (800 mg, 0.021 mol) was placed in a dry, 250 ml, three-necked,roundbottom flask, equipped with thermometer, mecanical stirring andaddition funnel. Under nitrogen, dry toluene (40 ml) was added followedby slow addition of THF (4 ml). A temperature at 15°-25° C. was assuredby the use of a water/ice-bath. After stirring for 30 minutes, the aboveamide (1.96 g, 0.0053 mol) was dissolved in dry toluene (10 ml) andslowly added to the LiAlH₄ -slurry, keeping the temperature at 20°-25°C. The reaction mixture was left stirring overnight at room temperature.Water (1 ml) was added dropwise, followed by 4N NaOH (1 ml) and finallywater (3 ml). The resulting precipitate was filtered off on filter aid(celite). The toluene solution was dried (MgSO₄) and the solvent wasremoved by evaporation in vacuo. The crude residue was purified bycolumn chromatography on silica gel (75 g), using a mixture of heptaneand ethyl acetate (1:1) as eluent. This afforded 0.9 g (61%) of theproduct, 3-(3-methoxy-10,11-dihydro-5H-dibenzob,f!azepin-5-yl)-1-propanol, as an oil. R_(f) : 0.25 (SiO₂ ;n-heptane/ethyl acetate=1:1).

The above alcohol (900 mg, 0.0032 mol) was dissolved in toluene (25 ml)and triethylamine (1.1 ml) was added. Methanesulfonyl chloride (1.0 ml,0.013 mol) was added dropwise and the reaction mixture was stirred for 2h. Water (100 ml) was added, followed by a further amount of toluene(100 ml) and the phases were separated. The organic phase was dried(MgSO₄) and the solvent evaporated in vacuo affording a residue whichwas dissolved in methyl ethyl ketone (50 ml). To this solution,(R)-3-piperidinecarboxylic acid ethyl ester tartrate (1.44 g, 0.0048mol) and potassium carbonate (1.1 g, 0.008 mol) were added and themixture was heated at reflux for 24 h, and left stirring at roomtemperature for 72 h. After filtration on filter aid (hyflo) the solventwas removed by evaporation in vacuo. The residue was purified by columnchromatography on silica gel (50 g) using a mixture of heptane and ethylacetate (1:1) as eluent. This afforded 0.2 g (14%) of1-(3-(3-methoxy-10,11-dihydro-5H-dibenzob,f!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl ester as anoil. R_(f) : 0.15 (SiO₂ ; n-heptane/ethyl acetate=1:1)

The above ester (190 mg, 0.00045 mol) was dissolved in ethanol (4 ml)and a solution of NaOH (0.1 g) in water (1 ml) was added. The mixturewas stirred at room temperature for 2 h. Concentrated HCl was addeduntil pH<1 (0.4 ml). Dichloromethane (100 ml) was added, followed bywater (50 ml) and the phases were separated. The organic phase was dried(MgSO₄) and the solvent evaporated in vacuo. The residue wasre-evaporated with acetone, ethyl acetate was added and the product wasfiltered and washed with diethyl ether. This afforded, after drying,0.13 g (67%) of the title compound as an amorphous product.

HPLC retention time=22.25 minutes. Calculated for C₂₄ H₃₀ N₂ O₃, HCl,2H₂ O: C, 61.74%; H, 7.50%; N, 6.00%; Found: C, 61.83%; H, 7.51%; N,5.98%.

EXAMPLE 17

(R)-1-(3-(10-Methyl-11-oxo-10,11-dihydro-5H-dibenzo b,e!1,4!diazepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid hydrochloride

To a solution of 11-oxo-10,11-dihydro-5H-dibenzo b,e! 1,4!diazepine (10g, 0.048 mol, Synthesis, (1985), 550) in dry dimethylformamide (100 ml)kept under an atmosphere of nitrogen, sodium hydride (2.1 g, 0.052 mol,60% dispersion in oil) was added, and the reaction mixture was stirredfor 1.5 h. Iodomethane (3.27 ml, 0.052 mol) was slowly added keeping thetemperature below 30° C. and the mixture was stirred overnight. Thereaction mixture was quenched with saturated ammonium chloride (20 ml)and poured onto ice water (300 ml). The solid was filtered off andwashed with plenty of water and dried. This yielded 10.4 g of crude10-methyl-11-oxo-10,11-dihydro-5H-dibenzo b,e! 1,4!diazepine which wasrecrystallised from methanol (200 ml), to give 6.7 g (63%) of10-methyl-11-oxo-10,11-dihydro-5H-dibenzo b,e! 1,4!diazepine. M.p.210°-211° C.

¹ H-NMR (200 MHz, DMSO-d₆) δ_(H) 3.37 (s, 3H, N--CH₃), 6.90 (t, 1H)6.97-7.14 (m, 4H), 7.24-7.36 (m, 2H), 7.66 (dd, 1H), 7.91 (bs, 1H, NH).

10-Methyl-11 -oxo-10,11-dihydro-5H-dibenzo b,e! 1,4!diazepine (5 g,0.022 mol) was dissolved in dry THF (50 ml) under an atmosphere ofnitrogen. n-Butyl lithium (9.1 ml, 0.025 mol, 23% solution in hexane)was slowly added with cooling on an ice bath and stirred for 30 minutes.A solution of 2-(3-bromo-1-propyloxy)tetrahydro-2H-pyran (6.28 g, 0.027mol) in dry THF (10 ml) was slowly added at room temperature. Thereaction mixture was heated to 60° C. for 1 h and stirred at roomtemperature overnight. The reaction mixture was quenched with saturatedammonium chloride (20 ml) and poured onto ice water (200 ml). Themixture was extracted with dichloromethane (3×150 ml). The combinedorganic extracts were washed with water (2×80 ml), dried (MgSO₄),filtered and the solvent evaporated in vacuo. This afforded a residue(9.8 g) which was purified by column chromatography on silica gel (900ml) using a mixture of dichloromethane and ethyl acetate (6:1) aseluent. This yielded 5.7 g (69%)10-methyl-5-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propyl)-5,10-dihydro-5H-dibenzob,e! 1,4!-diazepin-11-one as an oil. R_(f) : 0.57 (SiO₂ ;Dichloromethane/ethyl acetate=8:2).

10-Methyl-5-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propyl)-5,10-dihydro-5H-dibenzob,e! 1,4!diazepin-11-one (5.6 g, 0.015 mol) was dissolved in a mixtureof glacial acetic acid (40 ml), THF (20 ml) and water (10 ml), and themixture was heated at 45° C. for 6 h. Water (200 ml) was added and themixture extracted with ethyl acetate (4×100 ml). The combined organicextracts were washed with water (4×100 ml), dried (MgSO₄), filtered andthe solvent evaporated in vacuo. This afforded a residue (5.3 g) whichwas purified by column chromatography on silica gel (500 ml) using amixture of ethyl acetate and n-heptane (3:1) as eluent. This afforded2.3 g (53%) of 10-methyl-5-(3-hydroxy-1-propyl)-5,10-dihydro-5H-dibenzob,e! 1,4!diazepin-11-one as white crystals. R_(f) : 0.34 (SiO₂ ; ethylacetate/n-heptane=3:1). M.p. 177°-178° C.

10-Methyl-5-(3-hydroxy-1-propyl)-5,10-dihydro-5H-dibenzo b,e!1,4!diazepin-11-one (2 g, 0.007 mol) was dissolved in a mixture of dryTHF (50 ml) and triethylamine (3 ml) under an atmosphere of nitrogen.Methanesulfonyl chloride (0.69 ml, 0.009 mol) in THF (10 ml) was addeddropwise and the reaction mixture was stirred for 1 h. The solvent wasremoved by evaporation in vacuo and the residue was dissolved indichloromethane (200 ml). The organic solution was washed with water(3×50 ml), dried (MgSO₄), filtered and the solvent evaporated in vacuo.This afforded 3.0 g 3-(11-oxo-10-methyl-10,11-dihydro-5H-dibenzo b,e!1,4!diazepin-5-yl)-1-propyl methanesulfonate as a syrup.

A mixture of the above methanesulfonate (2.5 g, 0.007 mmol),(R)-3-piperidinecarboxylic acid ethyl ester tartrate (2.56 g, 0.0083mol) and dry potassium carbonate (5.81 g, 0.042 mol) in methyl ethylketone (50 ml) was heated at reflux temperature for 60 h under anatmosphere of nitrogen. The reaction mixture was filtered and the filtercake washed with plenty of ethyl acetate. The combined organic phaseswere washed with saturated ammonium chloride (1×100 ml), water (2×100ml), brine (1×50 ml), dried (MgSO₄), filtered and the solvent evaporatedin vacuo. The crude product 3.13 g of(R)-1-(3-(10-methyl-11-oxo-10,11-dihydro-5H-dibenzo b,e!1,4!-diazepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid ethyl esterwas used without further purification.

The above ester (2.5 g, 0.006 mol) was dissolved in a mixture of ethanol(20 ml) and water (10 ml). Sodium hydroxide (0.3 g, 0.007 mol) was addedand the reaction mixture stirred overnight at room temperature. Water(300 ml) was added and the mixture was washed with diethyl ether (2×100ml) and ethyl acetate (1×100 ml). The aqueous phase was acidified withconcentrated HCl (2.2 ml) and washed with dichloromethane (3×100 ml).Evaporation of the water gave a foam which was trituated with a mixtureof acetone and 2-propanol (1:1) (3×50 ml) and evaporated in vacuo. Theresidue was dissolved in a mixture of acetone (100 ml) and 2-propanol(30 ml). Diethyl ether (100 ml) was added and the mixture was stirredovernight. The precipitate was filtered off and washed with diethylether and dried in vacuo to give 1.14 g (45%) of the title compound aswhite crystals.

M.p. 204°-206° C. Calculated for C₂₃ H₂₇ N₃ O₃,HCl, 7/4 H₂ O: C, 59.86%;H, 6.88%; N, 9.11%; Found C, 59.93%; H, 6.97%; N, 8.97%;

EXAMPLE 18

(R)-1-(3-(9(H)-Oxo-10H-acridin-10-yl)-1-propyl)-3-piperidinecarboxylicacid hydrochloride

To a solution of acridone (15 g, 0.077 mol) in dry dimethylformamide(200 ml), sodium hydride (3.7 g, 0.092 mol, 60% dispersion in mineraloil) was added in 4 portions under an atmosphere of nitrogen. Thereaction mixture was stirred until gas evolution had ceased. A solutionof 2-(3-bromo-1-propyloxy)tetrahydro-2H-pyran (21.7 g, 0.092 mol) in drydimethylformamide (100 ml) was added dropwise. The reaction mixture washeated to 80° C. for 4 h and stirred overnight at room temperature. Thereaction mixture was poured onto ice water (800 ml) and extracted withethyl acetate (4×200 ml). The combined ethyl acetate extracts werewashed with water (3×300 ml), dried (MgSO₄), filtered and the solventevaporated in vacuo. The residue was dissolved in diethyl ether (150 ml)and unchanged starting material was filtered off. The solvent wasevaporated in vacuo and the residue was crystallised from 96% ethanol(150 ml), filtered and washed with ethanol (96%, 30 ml) and diethylether (50 ml). This procedure was repeated twice, yielding 8.5 g (33%)of 10-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propyl)acridin-9-one asyellowish crystals. M.p. 140.5°-141.5° C.

¹ H-NMR (200 MHz, CDCl₃) δ_(H) 1.50-2.00 (m, 6 H), 2.22 (m, 2H), 3.61(m, 2H), 3.97 (m, 2H), 4.53 (dt, 2H), 4.63 (t, 1H), 7.24-7.32 (dd, 2H),7.61-7.76 (m, 4H), 8.58 (dd, 2H).

10-(3-(Tetrahydro-2H-pyran-2-yloxy)-1-propyl)acridin-9-one wastransformed into the title compound using the same procedure asdescribed in Example 17.

M.p.>280° C. ¹ H-NMR (400 MHz, DMSO-d₆) δ_(H) 1.48 (bs, 1H), 1.89 (bm,2H), 2.02 (bd, 1H), 2.30 (bs, 2H), 2.98 (bd, 2H), 3.42 (bm, 4H), 3.62(bs, 1H), 4.57 (t, 2H, N--CH₂ --CH₂ --), 7.37 (t, 2H), 7.86 (dt, 2H),7.97 (d, 2H), 8.38 (dd, 2H), 11.00 (bs, 1H), 12.85 (bs, 1H).

We claim:
 1. A compound of formula I ##STR3## wherein R¹ and R²independently are hydrogen, halogen, trifluoromethyl, C₁₋₆ -alkyl orC₁₋₆ -alkoxy;Y is >N--CH₂ --, wherein only the underscored atomparticipates in the ring system; X is --NR⁹ --(C═O)-- wherein R⁹ ishydrogen or C₁₋₆ -alkyl; r is 1, 2, or 3; m is 1 or 2; n is 1 when m is1 and n is 0 when m is 2; R⁴ and R⁵ are hydrogen when m is 1; R⁴ and R⁵are hydrogen or form a bond when m is 2; and R⁶ is OH or C₁₋₈ -alkoxy;ora pharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein m is
 1. 3. A compound according to claim 1, wherein mis
 2. 4. A compound according to claim 1 whichis(R)-1-(3-(10-Methyl-11-oxo-10,11-dihydro-5H-dibenzo b,e!1,4!diazepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid; orapharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundaccording to claim 1 together with a pharmaceutically carrier ordiluent.
 6. The pharmaceutical composition according to claim 5, whereinthe compound is present in an amount between 0.5 mg and 1000 mg per unitdose.
 7. A method of treating neurogenic inflammation, migraine ordiabetic neuropathy in a subject in need of such treatment comprisingadministering to the subject a pharmaceutical composition according toclaim
 5. 8. A method of treating neurogenic inflammation, migraine ordiabetic neuropathy in a subject in need of such treatment comprisingadministering to the subject an effective amount of a compound accordingto claim
 1. 9. A compound of formula I ##STR4## wherein R¹ and R²independently are hydrogen, halogen, trifluoromethyl, C₁₋₆ -alkyl orC₁₋₆ -alkoxy;Y is>N--CH₂ --, wherein only the underscored atomparticipates in the ring system; X is --O--CH₂ --; r is 1, 2, or 3; m is1; n is 1; R⁴ and R⁵ are hydrogen; and R⁶ is OH or C₁₋₈ -alkoxy; orapharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundaccording to claim 9 together with a pharmaceutically carrier ordiluent.
 11. The pharmaceutical composition according to claim 10,wherein the compound is present in an amount between 0.5 mg and 1000 mgper unit dose.
 12. A compound which is(R)-1-(3-(11H-10-Oxa-5-aza-5H-dibenzoa,d!cyclohepten-5-yl)-1-propyl)-3-piperidinecarboxylic acid or apharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundaccording to claim 12 together with a pharmaceutically carrier ordiluent.
 14. The pharmaceutical composition according to claim 13,wherein the compound is present in an amount between 0.5 mg and 1000 mgper unit dose.
 15. A method of treating neurogenic inflammation,migraine or diabetic neuropathy in a subject in need of such treatmentcomprising administering to the subject an effective amount of acompound of formula I ##STR5## wherein R¹ and R² independently arehydrogen, halogen, trifluoromethyl, C₁₋₆ -alkyl or C₁₋₆ -alkoxy;Y is>N--CH₂ --, wherein only the underscored atom participates in the ringsystem; X is --O--CH₂ --; r is 1, 2, or 3; m is 1 or 2; n is 1 when m is1 and n is 0 when m is 2; R⁴ and R⁵ are hydrogen when m is 1; R⁴ and R⁵are hydrogen or form a bond when m is 2; and R⁶ is OH or C₁₋₈ -alkoxy;ora pharmaceutically acceptable salt thereof.